Rexulti (brexpiprazole) for Alzheimer's agitation: state of practice

The context

Approximately 5 to 6 million Americans have Alzheimer's disease. Behavioral disturbances including agitation, aggression, and restlessness affect roughly 40 to 50 percent at some point. These behaviors are among the leading reasons for nursing home placement and are highly distressing to caregivers.

Until 2023, no drug had FDA approval specifically for Alzheimer's agitation. Antipsychotics (risperidone, quetiapine, olanzapine, haloperidol) were used off-label. All carry an FDA boxed warning for increased mortality in dementia-related psychosis (roughly 1.7 fold), plus stroke risk warnings.

Brexpiprazole's approval was based on Phase 3 trials showing statistical improvement in Cohen-Mansfield Agitation Inventory (CMAI) scores over 12 weeks.

Trial data

Study 213 and Study 3-101:

• 12-week randomized placebo-controlled trials
• Adult patients with Alzheimer's dementia and clinically significant agitation
• Brexpiprazole 2 or 3 mg daily vs placebo
• Primary endpoint: change in Cohen-Mansfield Agitation Inventory (CMAI)
• Effect size: statistically significant reduction in agitation
• Adverse events: somnolence, headache, urinary tract infections, weight gain, insomnia

Discontinuation rates for adverse events were modest. Falls and injuries occurred at rates similar to placebo. Boxed warning for mortality still applies.

Dosing

• Start at 0.5 mg once daily
• Titrate to 1 to 3 mg once daily based on response and tolerability
• Approved dose range for Alzheimer's agitation: 2 to 3 mg daily
• No renal or hepatic dose adjustment for mild to moderate impairment
• Reduce dose with concurrent CYP2D6 or CYP3A4 strong inhibitors

Boxed warning

Same all-cause mortality warning that applies to all antipsychotics in dementia-related psychosis. Studies of atypical antipsychotics in this population showed 1.6 to 1.7 fold increased mortality (about 4.5 percent vs 2.6 percent over 10 weeks). Causes typically cardiovascular or infectious.

The approval does not eliminate this warning. It provides a specific indication for a specific problem, allowing informed use rather than off-label use, but the risk framework remains.

Where it fits

First-line: non-drug interventions:

• Environmental modification
• Caregiver education and support
• Address underlying causes (pain, infection, medication side effects, sleep, boredom)
• Music therapy, reminiscence, engagement activities
• Consistent routines

When medication is warranted (severe or dangerous agitation):

• Rexulti has the specific FDA indication
• Aripiprazole, risperidone, quetiapine remain reasonable alternatives (off-label)
• Cobenfy (xanomeline-trospium) may be considered given no D2 blockade, though dementia data is still emerging

Comparison with alternatives:

• Vs risperidone: similar effect size, lower EPS risk
• Vs quetiapine: comparable, less sedation with brexpiprazole
• Vs Cobenfy: mechanism different; brexpiprazole is a D2 partial agonist plus 5-HT1A partial agonist plus 5-HT2A antagonist; Cobenfy is muscarinic M1/M4 agonist

Cost and access

Rexulti list price around $1,500 per month. Insurance coverage variable. Medicare Part D coverage common. Manufacturer assistance program for eligible patients.

Common questions

Does Rexulti really work for Alzheimer's agitation? Trial data shows modest but statistically significant improvement. Effect size is small (2-3 points on CMAI). Not a dramatic difference from placebo, but real for many patients.

Is Rexulti safer than other antipsychotics for elderly? Similar overall safety profile. Boxed warning applies. Some evidence of lower EPS than risperidone. Not clearly safer than quetiapine.

Should I start with Rexulti or try something else first? Non-drug interventions first. If medication is needed, Rexulti has the specific indication which is a real advantage for informed prescribing. Alternatives (aripiprazole, quetiapine, risperidone at low dose) remain reasonable.

How long should treatment continue? Reassess every 3 months. Trials of dose reduction and discontinuation appropriate in stable patients. Many dementia patients tolerate discontinuation.

Does Rexulti affect the underlying Alzheimer's disease? No. It treats behavioral symptoms only. Disease-modifying therapy (lecanemab, donanemab) is a different intervention for a different question.

Can it be used in patients with Lewy body dementia or Parkinson's disease dementia? Off-label. Traditional antipsychotics can worsen parkinsonism in these patients. Pimavanserin and clozapine at low dose are preferred in these populations.

What about vascular dementia? Off-label for vascular dementia agitation. Same boxed warning applies. Reasonable considered use with informed decision-making.

Sources

• Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia: two 12-week randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400.
• Rexulti (brexpiprazole) prescribing information updated June 2023 for Alzheimer's agitation indication.
• FDA Public Health Advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances. April 2005.
• Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173(5):543-546.